tbuckley/cabot-search huggingface dataset:
Return to sport following low-risk and high-risk bone stress injuries: a systematic review and meta-analysis
Authors: Tim Hoenig, Julian Eissele, André Strahl, Kristin L Popp, Julian Stürznickel, Kathryn E Ackerman, Karsten Hollander, Stuart J Warden, Karl-Heinz Frosch, Adam S Tenforde, Tim Rolvien
Journal: British Journal of Sports Medicine (2023)

Objective Bone stress injuries (BSIs) are classified in clinical practice as being at low- or high-risk for complication based on the injury location. However, this dichotomous approach has not been sufficiently validated. The purpose of this systematic review was to examine the prognostic role of injury location on return-to-sport (RTS) and treatment complications after BSI of the lower extremity and pelvis. Design Systematic review and meta-analysis. Data sources PubMed, Web of Science, Cochrane CENTRAL and Google Scholar databases were searched from database inception to December 2021. Eligibility criteria for selecting studies Peer-reviewed studies that reported site-specific RTS of BSIs in athletes. Results Seventy-six studies reporting on 2974 BSIs were included. Sixteen studies compared multiple injury sites, and most of these studies (n=11) described the anatomical site of injury as being prognostic for RTS or the rate of treatment complication. Pooled data revealed the longest time to RTS for BSIs of the tarsal navicular (127 days; 95% CI 102 to 151 days) and femoral neck (107 days; 95% CI 79 to 135 days) and shortest duration of time for BSIs of the posteromedial tibial shaft (44 days, 95% CI 27 to 61 days) and fibula (56 days; 95% CI 13 to 100 days). Overall, more than 90% of athletes successfully returned to sport. Treatment complication rate was highest in BSIs of the femoral neck, tarsal navicular, anterior tibial shaft and fifth metatarsal; and lowest in the fibula, pubic bone and posteromedial tibial shaft. Conclusion This systematic review supports that the anatomical site of BSIs influences RTS timelines and the risk of complication. BSIs of the femoral neck, anterior tibial shaft and tarsal navicular are associated with increased rates of complications and more challenging RTS. PROSPERO registration number CRD42021232351.
Advisory Board and Contents
Authors: Xin Koh, Jun Pek, Yunyi Gao, Therese Solberg, Chundi Wang, Feng Gao, Qingping Yao, Peter Gorevic, Bo Shen, Greg Gibson, Kateryna Makova, Matthias Weissensteiner, Bingbing Ren, Min-Xin Guan, Tianhua Zhou, Xiujun Cai, Ge Shan, Guido Van Mierlo, Olga Pushkarev, Judith Kribelbauer, Bart Deplancke, Iliano Coutinho-Abreu, Omar Akbari
Journal: Trends in Genetics (2023)
Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology
Authors: Wenhui Qiao, Yixing Chen, Jun Zhong, Benjamin J. Madden, Cristine M. Charlesworth, Yuka A. Martens, Chia-Chen Liu, Joshua Knight, Tadafumi C. Ikezu, Aishe Kurti, Yiyang Zhu, Axel Meneses, Cassandra L. Rosenberg, Lindsey A. Kuchenbecker, Lucy K. Vanmaele, Fuyao Li, Kai Chen, Francis Shue, Maxwell V. Dacquel, John Fryer, Akhilesh Pandey, Na Zhao, Guojun Bu
Journal: Molecular Neurodegeneration (2023)

Abstract Background The rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimer’s disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies. Methods We generated a novel Trem2 H157Y knock-in mouse model through CRISPR/Cas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, immunofluorescent staining, in vivo micro-dialysis, and cortical bulk RNA sequencing. Results Consistent with previous in vitro findings, Trem2 H157Y increases TREM2 shedding with elevated soluble TREM2 levels in the brain and serum. Moreover, Trem2 H157Y enhances synaptic plasticity without affecting microglial density and morphology, or TREM2 signaling. In the presence of amyloid pathology, Trem2 H157Y accelerates amyloid-β (Aβ) clearance and reduces amyloid burden, dystrophic neurites, and gliosis in two independent founder lines. Targeted mass spectrometry analysis of TREM2 revealed higher ratios of soluble to full-length TREM2-H157Y compared to wild-type TREM2, indicating that the H157Y mutation promotes TREM2 shedding in the presence of Aβ. TREM2 signaling was further found reduced in Trem2 H157Y homozygous mice. Transcriptomic profiling revealed that Trem2 H157Y downregulates neuroinflammation-related genes and an immune module correlated with the amyloid pathology. Conclusion Taken together, our findings suggest beneficial effects of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD risk, we speculate TREM2 H157Y in humans might increase AD risk through an amyloid-independent pathway, such as its effects on tauopathy and neurodegeneration which merit further investigation.
Author Correction: A shared disease-associated oligodendrocyte signature among multiple CNS pathologies
Authors: Mor Kenigsbuch, Pierre Bost, Shahar Halevi, Yuzhou Chang, Shuo Chen, Qin Ma, Renana Hajbi, Benno Schwikowski, Bernd Bodenmiller, Hongjun Fu, Michal Schwartz, Ido Amit
Journal: Nature Neuroscience (2023)
Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network
Authors: Zihan Yang, Li Zhou, Tongxu Si, Siyuan Chen, Chengxi Liu, Kelvin Kaki Ng, Zesheng Wang, Zhiji Chen, Chan Qiu, Guopan Liu, Qingliang Wang, Xiaoyu Zhou, Liang Zhang, Zhongping Yao, Song He, Mengsu Yang, Zhihang Zhou
Journal: Molecular Cancer (2023)

Abstract Background Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear. Methods LC–MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC–MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype. Results Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis. Conclusions LH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.
Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary
Authors: Atara Posner, Tharani Sivakumaran, Andrew Pattison, Dariush Etemadmoghadam, Niko Thio, Colin Wood, Krista Fisher, Samantha Webb, Anna DeFazio, Nicholas Wilcken, Bo Gao, Christos S Karapetis, Madhu Singh, Ian M Collins, Gary Richardson, Christopher Steer, Mark Warren, Narayan Karanth, Andrew Fellowes, Stephen B Fox, Rodney J Hicks, Penelope Schofield, David Bowtell, Owen W J Prall, Richard William Tothill, Linda Mileshkin
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs. Methods Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed. Results A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (&gt;10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p&lt;0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease. Conclusions A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.
Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 mAb on breast cancers
Authors: Hongping Ba, Zigang Dai, Zunyue Zhang, Peng Zhang, Bingjiao Yin, Jing Wang, Zhuoya Li, Xiaoxi Zhou
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies. Methods We generated CAR-T cells targeting tmTNF-α but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF-α-expressing breast cancer cells in vitro and in vivo. Results Our tmTNF-α CAR-T cells showed potent cytotoxicity against tmTNF-α-expressing breast cancer cells but not tmTNF-α-negative tumor cells with increased secretion of interferon gamma (IFN-γ) and interleukin (IL)-2 in vitro. In tmTNF-α-overexpressing TNBC-bearing mice, the tmTNF-α CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN-γ and IL-2. However, we found thattmTNF-α induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF-κB and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF-α CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy. Conclusion Our findings suggest a potent antitumor efficacy of the tmTNF-α CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF-α signaling, indicating a promising individual therapy for tmTNF-α-positive breast cancers including TNBC.
Dementia prevention in memory clinics: recommendations from the European task force for brain health services
Authors: Giovanni B. Frisoni, Daniele Altomare, Federica Ribaldi, Nicolas Villain, Carol Brayne, Naaheed Mukadam, Marc Abramowicz, Frederik Barkhof, Marcelo Berthier, Melanie Bieler-Aeschlimann, Kaj Blennow, Andrea Brioschi Guevara, Emmanuel Carrera, Gaël Chételat, Chantal Csajka, Jean-François Demonet, Alessandra Dodich, Valentina Garibotto, Jean Georges, Samia Hurst, Frank Jessen, Miia Kivipelto, David J. Llewellyn, Laura McWhirter, Richard Milne, Carolina Minguillón, Carlo Miniussi, José Luis Molinuevo, Peter M. Nilsson, Alastair Noyce, Janice M. Ranson, Oriol Grau-Rivera, Jonathan M. Schott, Alina Solomon, Ruth Stephen, Wiesje van der Flier, Cornelia van Duijn, Bruno Vellas, Leonie N.C. Visser, Jeffrey L. Cummings, Philip Scheltens, Craig Ritchie, Bruno Dubois
Journal: The Lancet Regional Health - Europe (2023)

Observational population studies indicate that prevention of dementia and cognitive decline is being accomplished, possibly as an unintended result of better vascular prevention and healthier lifestyles. Population aging in the coming decades requires deliberate efforts to further decrease its prevalence and societal burden. Increasing evidence supports the efficacy of preventive interventions on persons with intact cognition and high dementia risk. We report recommendations for the deployment of second-generation memory clinics (Brain Health Services) whose mission is evidence-based and ethical dementia prevention in at-risk individuals. The cornerstone interventions consist of (i) assessment of genetic and potentially modifiable risk factors including brain pathology, and risk stratification, (ii) risk communication with ad-hoc protocols, (iii) risk reduction with multi-domain interventions, and (iv) cognitive enhancement with cognitive and physical training. A roadmap is proposed for concept validation and ensuing clinical deployment.
Tests for Carcinoembryonic Antigen
Authors: Phil Gold
Journal: JAMA (1975)

THE CARCINOEMBRYONIC antigen (CEA) of the human digestive system was first described in 1965 after a series of experiments involving the immunization of heterologous animals with human-colon cancer-tissue extracts and the preparation of antitumor antisera under well-defined conditions. The CEA has been purified, identified as a fairly large glycoprotein, and partly characterized with regard to its protein and carbohydrate constituents. Several review articles<sup>1-4</sup>detail these developments. At least a portion of the CEA of colon cancer cells has been localized, by immunoelectron microscopy, to the cellular glycocalyx.<sup>1</sup>From this position, where it may represent a structural constituent of the glycocalyx or material in transit from the cytoplasm across the cell membrane, the CEA is apparently quite easily released into the surrounding body fluids. <h3>Radioimmunoassay Techniques</h3> Since 1969, a number of sensitive and reproducible radioimmunoassays for CEA have been developed that are capable of detecting nanogram quantities of this
A Health Questionnaire Based on Paper-and-Pencil Medium Individualized and Produced by Computer
Authors: Maurice J. Martin
Journal: JAMA (1969)

A computer-generated and computer-processed health questionnaire has been evaluated for patient acceptance and reliability of content. Various formats have been tested and it was concluded that a mark-sense paper-and-pencil questionnaire offered significant advantages over a cardsort questionnaire. Studies of administration techniques showed that administration by a specially trained clerk is advantageous.
Migraine Prevention With Timolol
Authors: Stanley Stellar
Journal: JAMA (1984)

One hundred seven patients (77 women and 30 men) with migraine headache were given prophylactic treatment with timolol maleate, 20 to 30 mg/day, or matching placebo during a 20-week, double-blind crossover study. Among the 94 patients who completed the study, timolol was significantly better than placebo in terms of decrease in frequency of headaches from baseline, numbers of patients who had a 50% reduction in headache frequency, global response, and patient preference. Overall global response rates were 65% with timolol compared with 40% with placebo. The severity and duration of headaches that occurred were unchanged. Few side effects were reported with either timolol or placebo. The study demonstrates that the β-blocker timolol is a safe and effective treatment in patients with frequent migraine headaches. (<i>JAMA</i>1984;252:2576-2580)
Mortality From Pneumonia and Risk Conditions During Influenza Epidemics
Authors: Albert B. Sabin
Journal: JAMA (1977)

Increases in mortality from pneumonia and high-risk chronic diseases have not occurred during recent influenza epidemics. Excess mortality during the past four influenza epidemics in the United States is attributable to influenza reported as a primary cause of death, and the average excess was only about 4,000 deaths per epidemic. Most clinical influenza severe enough to cause hundreds of millions of days of bed disability during nonepidemic as well as epidemic years is not caused by the influenza viruses. During the nonepidemic year of 1973 to 1974, there were 61,841,000 episodes of clinical influenza severe enough to put people to bed for an average of 3.6 days. In my judgment there is now no basis for recommending annual administration of influenza vaccines to so-called high-risk groups and persons over 64 years of age. (<i>JAMA</i>237:2823-2828, 1977)
Spontaneous Rupture of the Esophagus (Boerhaave Syndrome)
Authors: T. Curtis Campbell
Journal: JAMA (1976)

SPONTANEOUS rupture of the esophagus, also called Boerhaave syndrome after the Dutch physician who first reported it in 1724,<sup>1</sup>was often undiagnosed or misdiagnosed in living patients, resulting in a fatal outcome. In Boerhaave syndrome, patients experience violent vomiting followed by severe chest pain, prostration, and, inevitably, death from the ruptured esophagus. This syndrome was formerly diagnosed only at autopsy.<sup>2-4</sup> Since Barrett's<sup>5</sup>report of the first successful surgical treatment of the condition in 1947, other reports and reviews, mostly in the surgical literature, have emphasized the necessity of early diagnosis and rapid medical and surgical treatment to ensure patient survival.<sup>6-13</sup> The major diagnostic problem is still that esophageal rupture is often not considered initially among possible diagnoses by the primary physician. Rather, the patient's symptoms are often misdiagnosed as being caused by acute myocardial infaction, ruptured peptic ulcer, pulmonary embolism, pancreatitis, or dissecting aortic aneurysm. Hence,
Field Trial of Live Attenuated Rubella Virus Vaccine During an Epidemic on Taiwan
Authors: J. Thomas Grayston
Journal: JAMA (1969)

Three experimental rubella vaccines derived from the HPV-77 attenuated strain were field tested in a placebo controlled trial for ability to prevent rubella during an epidemic on Taiwan. A total of 3,259 doses of the vaccines and 2,735 doses of placebo were given in March 1968 to boys in grades 1 through 4 in two schools each in Taipei and Taichung, Taiwan. Twice weekly surveillance for rash disease in the placebo and uninoculated children showed, by the end of June, cumulative attack rates of more than 50% in Taipei and 20% in Taichung. There was a sharp drop in rash cases among boys receiving vaccine between two and three weeks after inoculation. Results showed an efficacy beginning three weeks following immunization for all three vaccines of 93% to 94% in the prevention of clinical rubella.
Association of Tafamidis With Health Status in Patients With ATTR Cardiac Amyloidosis
Authors: Brett W. Sperry, Mazen Hanna, Mathew S. Maurer, Jose Nativi-Nicolau, Lysbeth Floden, Michelle Stewart, Kathleen W. Wyrwich, Alexandra I. Barsdorf, Heli Kapadia, John A. Spertus
Journal: JAMA Cardiology (2023)

Importance Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms. Objective To evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms. Design, Setting, and Participants This randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries. Interventions Tafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo. Main Outcomes and Measures Established thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class. Results Among 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P &amp;amp;lt; .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo. Conclusions and Relevance In ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo. Trial Registration ClinicalTrials.gov Identifier: NCT01994889
Transportation Noise and Risk of Tinnitus: A Nationwide Cohort Study from Denmark
Authors: Manuella Lech Cantuaria, Ellen Raben Pedersen, Aslak Harbo Poulsen, Ole Raaschou-Nielsen, Ulla Arthur Hvidtfeldt, Gregor Levin, Steen Solvang Jensen, Jesper Hvass Schmidt, Mette Sørensen
Journal: Environmental Health Perspectives (2023)

There is a growing body of evidence linking residential exposure to transportation noise with several nonauditory health outcomes. However, auditory outcomes, such as tinnitus, are virtually unexplored.